Autoimmune thyroid disease: old and new players

1. Autoimmune thyroid disease: old and new players DeMarco, V. G. et al. Nat. Rev. Endocrinol. 10, 364–376 (2014)

2. Introduction • Autoimmune thyroid disease (AITD) is a multifactorial or so-called ‘complex’ disease in which autoimmunity against thyroid antigens develops against a particular genetic background facilitated by exposure to environmental factors • AITD encompasses a spectrum of conditions ranging from Hashimoto’s hypothyroidism (HH) at one end to Graves’ hyperthyroidism (GH) at the other end • Thyroid peroxidase (TPO) and thyroglobulin (Tg) are the major autoantigens in Hashimoto’s disease, but TPO-Ab and Tg-Ab occur also in ~70% of patients with Graves’ disease

3. Introduction This review focuses on what has been learnt in the last 10 years on the etiology of AITD: • Is the predilection for female gender better understood? • Have new susceptibility genes been detected? And has progress been made with respect to environmental insults? • Have there been new players in this field, or have remaining issues with old players been clarified? • Finally, if individuals are at risk to develop AITD in view of their family history of AITD, is there anything they can do in terms of AITD prevention?

4. Existential factors: Parity • Parity as a risk factor for AITD has received much attention in relation to fetal microchimerism • There is transfer of fetal cells into the maternal circulation, already in the first trimester • Fetal microchimerism results when fetal cells persist in maternal tissues, and it is hypothesized that maternal immune responses against foreign fetal antigens might trigger autoimmune diseases • Fetal microchimerism has indeed been found in blood and thyroid tissue from women with Hashimoto’s or Graves’ disease

5. Existential factors: Parity • Using parity as a surrogate for increasing fetal cell exposure, one would expect the higher the number of pregnancies is, the higher the frequency and/or concentration of thyroid antibodies will be • However, the results have been conflicting • Several population-based studies have observed that there was no association between parity and TPO-Ab any longer after adjustment for maternal age and other important confounders • Other equally large studies do report associations that remain significant after adjustments, using higher cutoff values for TPO-Ab positivity

6. Existential factors: X-chromosome inactivation • A skewed X-chromosome inactivation (XCI) is defined – arbitrarily – as inactivation of the same X chromosome in ≥80% of cells • The consequence could be that self-antigens on one X chromosome are not expressed at sufficiently high levels in the thymus or at peripheral sites involved in tolerance induction • Loss of immunological tolerance to X-linked antigens might induce autoimmunity • The epigenetic phenomenon of skewed XCI may, in part, explain the strong female preponderance in AITD

7. Genetic factors • Single-nucleotide polymorphisms (SNPs) in TSHR have been specifically associated with Graves’ disease and not with autoimmune hypothyroidism in a Caucasian population • The functional consequences of these intronic SNPs are not entirely clear • They could give rise to RNA splice variants, increasing the level of potential autoantigenic TSHR-A subunits • Alternatively, SNP carriers may have fewer thymic TSHR mRNA transcripts, which may decrease central tolerance to TSHR

8. Genetic factors • The immunoregulatory genes HLA class II, CTLA4, and PTPN22 were already recognized as risk factors in the 20th century by case–control studies • They are all involved in the immunological synapse, in which antigenic peptides complexed in HLA molecules are presented by antigen-presenting cells to T-cell receptors on T-cells • Polymorphisms in these genes are not specific for AITD, as they also confer susceptibility for other autoimmune diseases

9. Environmental factors: New players • Smoking is a well-established risk factor for Graves’ disease • The OR for GH is 3.30 (95% CI, 2.09–5.22) in current smokers when compared with never smokers • The OR for Graves’ ophthalmopathy is even higher: OR 4.40 (95% CI, 2.88–6.73) in ever smokers vs never smokers • In the last few years, however, convincing evidence has been obtained that current smoking protects against (autoimmune) hypothyroidism • Although smoking is an old player in the relation between environmental exposures and autoimmunity, the discovery of its protective effect allows the label ‘new player’

10. Environmental factors: New players • Alcohol is known to protect against other autoimmune diseases such as rheumatoid arthritis and type 1 diabetes • However, the effect of alcohol on the immune system is complex, and how alcohol suppresses autoimmunity remains incompletely understood • A Cochrane systematic review concludes that data at present do not allow confident decision making about the use of selenium supplementation for Hashimoto’s thyroiditis • Low vitamin D levels have been identified as a risk factor for various autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, & Crohn’s disease. The situation with respect to AITD is less clear

11. Environmental factors: Old players • Thyroid antibodies and autoimmune hypothyroidism are more common in iodine-replete areas than in iodine-deficient areas • Further elegant proof of this has recently been obtained from population-based studies in Denmark • Prevalence figures before and after mandatory iodization of salt were 14.3 and 23.8% for TPO-Ab, and 13.7 and 19.9% for Tg-Ab respectively; ORs were 1.80 (TPO-Ab) and 1.49 (Tg-Ab) • In contrast to Graves’ disease, stress is apparently not involved in Hashimoto’s thyroiditis

12. Natural history of AITD and prevention

13. Possible preventive interventions to decrease risk of developing autoimmune thyroid disease